Halogenated olefin pyridine derivatives



Patented Nov. 4, 1952 HALOGENATED OLE-FIN PYRIDINE DERIVATIVES James M.Smith, -Jr., North l lainfield, N. J., as-

signor to American Cyanamid Company, New

York, Nr Y., a corporation of Maine No Drawing. Application June 18,1949,

. Serial No. 100,099

3 Claims. (Cl- 260-240) This invention relates tonew organiccompyridines. This application is a continuationi'n-part of myapplications Serial No. {724,237 filed January 24, 1947, now U. S.Patent 2,482,521, issued September 20, 1949 and Serial No. 725,733,filed January 31,1947, now US. Patent 2,512,180, issued June 20, 1950which are both continuations-in-part .of my Serial No. 598,627, filedJune 9, 1945 and now U. S. Patent No. 2,442,865, issued June 8, 1948.

The new compounds of the present invention have the following formula inwhich R. is a pyridine or quinoline radical.

These chloro products are useful as therapeutic agents since theypossess anti-convulsant properties, and are also intermediates in thepreparation of the compounds described in my U. S. Patents 2,482,521 and2,512,180 and other useful organic compounds.

The compounds are white to pale yellow crystalline solids and aregenerally soluble in organic solvents such as alcohol. The acid salts ofthe compounds are water-soluble.

The preferred synthesis of the products of my invention is that in whichp-chlorobenzal-dehyde is condensed with a methyl pyridine or quinoline.The reaction is carried out at elevated temperatures in the range 50-250C. A reaction period of from 2-20 hours is sufiicient to assure adequateyields in most cases. I

When the chloro-styryl pyridine derivatives are being preparedconvenient starting materials are para-chlorobenzaldehyde and alphaorgamma-picoline. When the analogous quincline derivatives are beingprepared, lepidine or quinaldine are used as raw materials.

The chloro-styryl heterocy-cle derivatives are isolated as the freebases or as acid salts, preferably the hydrochloride. Recrystallizationof the acid salts from water ofi-ers a convenient limited by thefollowing examples. Unless otheri wise stated, all parts are by weight.

EXAMPLE 1 1- (p-chloiophenyl) -2- (Ii-pyridyl) ethylene mixture of 1500parts of p-chlorobenzalde pounds, ancl'more particularlyto'chloro-styryl hyde, 990 parts of alpha-picoline, and 1088 parts ofacetic" anhydride are heated under refiux in an atmosphere of nitrogenfor 18 hours. Low boiling products and unreacted. ingredients are thenremoved by vacuum distillation until approximately 1500 parts of.distillate are obtained. The residue is poured into several volumes ofcold waterresultingin the precipitation of a brown crystalline solidwhich is isolated by filtration. This is dissolved in an excess of 2Nhydrochloric acid and extracted with ether or benzene to removeimpurities. The acid solution is then neutralized with caustic, and theresulting precipitate filtered off, washed with water and dried. Theyield of crude l-(p-chlorophenyl 2 (2 pyridyl) ethylene is approximately1245 parts. Purification of the product may be accomplished byrecrystallization of the base or its hydrochloride from a suitableorganic solvent such as alcohol, with the aid of decolorizing charcoal,or by vacuum distillation of the base which boils at 173-180 C./5-7 mm.The purified base melts at 83-84 C. and the hydrochloride melts at193-l95 C.

. EXAMPLE 2 1 (p-chlorophenyl) -2- (st-pyridyl) ethylene A mixture of600 parts of p-chlorobenzaldehyde, 396 parts of a-picol-ine and 435parts of acetic anhydri-de are heated to reflux in an atmosphere ofnitrogen for 6 hours. On heating, a crystalline mass is formed which isdrowned in several volumes of water and filtered. The filter cake isdissolved in an excess of warm dilute hydrochloric acid and refilteredto remove the small amount of insoluble material. On cooling to 10 C. aheavy precipitate is formed which is filtered off and then slurried inacetone to remove dark colored impurities. On refiltering and drying,approximately 671 parts of l-Kp-chlorophenyl)-2-(4pyridyl) ethylenehydrochloride is obtained which is a yellow product melting at 248-250C. The free base pre- ,pared by neutralizing an aqueous solution of thehydrochloride with caustic melts at approximately 110 C.

EXAMPLE 3 2- (p-chlo-rophenyl) -2- (Z-quinolyl) ethylene A mixture of760 parts of quinaldine, 530 parts of p-chlorobenzaldehyde and 357 partsacetic anhydride are boiled under reflux for 2 hours under a nitrogenatmosphere. The solution is allowed to cool, whereupon it solidifies.After 16 hours it is melted and poured into an ice and water mixture togive a total volume of 4000 parts. The crude product is collected on thefilter and washed until the wash-water is acid Iree. The filtrate isthen extracted with 6300 a parts of boiling alcohol containing a smallamount of activated carbon. The alcohol extract, on filterin andcooling, deposits a yellow crystalline product which is collected on thefilter, washed with cool alcohol and dried. The filtrate and washingsare used to extract the crude residue 3 times more in a similar fashion.The total recovery is 654 parts. A sample of the base recrystallizedfrom boiling alcohol then melted at 142.8-143.2 C.

EXAMPLE 4 1 (p-chZov'op'heng l) -2- (4-quinolyl) ethylene A mixture of702.5 parts of p-chlorobenzaldehyde, 770 parts of lepidine and 510 partsof acetic anhydride was refluxed for 10 hours. It was then cooled,poured into water, and the water decanted from theresultant crystallinemass. ing ethanol to give 625. parts of the product melting at126.0-127.3 C. After repeated recrystallization from ethanol includingdecolor- The latter was recrystallized from boil-.

4 ization with activated charcoal, melted at 127.0'128.1 C.

I claim: ,1. Compounds of the formula where R, is a pyridine radical.

2. l-(l-chlorostyryl) pyridine. 3. 2(4-chlorostyryl) pyridine.

JAMES M. SMITH, JR.

the product REFERENCES CITED The following references are of record inthe file of this patent:

v UNITED STATES PATENTS Number Name Date 2,028,141 Ackerman Jan. 21,1936 2,255,077 Middleton Sept. 9. 1941 2,388,499 Ruthof Nov. 6, 19452,427,286 Knapp Sept. 9, 194

1. COMPOUNDS OF THE FORMULA